Influence of insulin on cholesterol removal from macrophages and cholesterol ester uptake by HepG2 cells.
The fact that an increased blood insulin level is observed in patients with coronary artery disease (CAD) confirms the hypothesis that insulin promotes the development of atherosclerosis. The low high-density lipoprotein (HDL) concentration observed in such patients may contribute to alteration in reverse cholesterol transport and promote the accumulation of sterols in vascular tissue. We examined the effect of insulin (20-1000 microU mL-1) on cholesterol efflux into HDL3 particles from human blood monocyte/macrophages and rat peritoneal macrophages preloaded with labelled cholesterol esters, and the influence of insulin on the accumulation of sterols by rat liver cells and HepG2 cell line in vitro models. Insulin at concentrations up to 250 microU mL-1 inhibited the efflux of cholesterol from rat macrophages and promoted high uptake of sterols by both types of hepatic cells. Pharmacological concentrations higher than 250 microU mL-1 exerted the opposite effect. In the case of human macrophages, an insulin concentration of 20 microU mL-1 increased cholesterol removal, whereas 100-200 microU mL-1 insulin inhibited cholesterol removal from cells, and very high concentrations (> 350 microU mL-1) again increased cholesterol removal. We have shown that insulin excess counteracts the beneficial effects of HDL in removing cellular cholesterol and, therefore, may promote development of atherogenesis.


Receptor-mediated inhibition of renal Na(+)-K(+)-ATPase is associated with endocytosis of its alpha- and beta-subunits.
The mechanisms involved in receptor-mediated inhibition of Na(+)-K(+)-ATPase remain poorly understood. In this study, we evaluate whether inhibition of proximal tubule Na(+)-K(+)-ATPase activity by dopamine is linked to its removal from the plasma membrane and internalization into defined intracellular compartments. Clathrin-coated vesicles were isolated by sucrose gradient centrifugation and negative lectin selection, and early and late endosomes were separated on a flotation gradient. Inhibition of Na(+)-K(+)-ATPase activity by dopamine, in contrast to its inhibition by ouabain, was accompanied by a sequential increase in the abundance of the alpha-subunit in clathrin-coated vesicles (1 min), early endosomes (2.5 min), and late endosomes (5 min), suggesting its stepwise translocation between these organelles. A similar pattern was found for the beta-subunit. The increased incorporation of both subunits in all compartments was blocked by calphostin C. The results demonstrate that the dopamine-induced decrease in Na(+)-K(+)-ATPase activity in proximal tubules is associated with internalization of its alpha- and beta-subunits into early and late endosomes via a clathrin-dependent pathway and that this process is protein kinase C dependent. The presence of Na(+)-K(+)-ATPase subunits in endosomes suggests that these compartments may constitute normal traffic reservoirs during pump degradation and/or synthesis.


A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis.
Creatine monohydrate (creatine) has potential neuroprotective properties and is a commonly used supplement in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Minimum therapeutic and maximum tolerated dosages of creatine are not yet known, nor is it known what systemic plasma concentrations result from specific dosage regimens. The objectives of this study were to establish steady-state plasma pharmacokinetics of creatine at several dosages, and to evaluate the effects of creatine on brain metabolites using proton magnetic resonance spectroscopy ((1)H-MRS). Six participants with ALS received creatine at three weekly escalating oral dosages (5, 10, and 15 g b.i.d.). Plasma creatine levels and MR spectra were obtained at baseline and with each dosage increase. Mean pre-dose steady-state creatine plasma concentrations were 20.3, 39.3, and 61.5 ug/ml at 5, 10, and 15 g b.i.d., respectively. Creatine spectra increased by 8% (p = 0.06) and glutamate + glutamine signals decreased by 17% (p = 0.039) at higher dosages. There were no safety concerns at any of the dosages. In conclusion, creatine plasma concentrations increased in a dose-dependent manner. Creatine appears to cross the blood-brain barrier, and oral administration of 15 g b.i.d. is associated with increased in vivo brain creatine concentrations and decreased glutamate concentrations.


TAT-MTS-MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM-deficient cells.
Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of the mitochondrial enzyme, methylmalonyl-CoA mutase (MCM). The main treatments for MMA patients are dietary restriction of propiogenic amino acids and carnitine supplementation. Liver or combined liver/kidney transplantation has been used to treat those with the most severe clinical manifestations. Thus, therapies are necessary to help improve quality of life and prevent liver, renal and neurological complications. Previously, we successfully used the TAT-MTS-Protein approach for replacing a number of mitochondrial-mutated proteins. In this targeted system, TAT, an 11 a.a peptide, which rapidly and efficiently can cross biological membranes, is fused to a mitochondrial targeting sequence (MTS), followed by the mitochondrial mature protein which sends the protein into the mitochondria. In the mitochondria, the TAT-MTS is cleaved off and the native protein integrates into its natural complexes and is fully functional. In this study, we used heterologous MTSs of human, nuclear-encoded mitochondrial proteins, to target the human MCM protein into the mitochondria. All fusion proteins reached the mitochondria and successfully underwent processing. Treatment of MMA patient fibroblasts with these fusion proteins restored mitochondrial activity such as ATP production, mitochondrial membrane potential and oxygen consumption, indicating the importance of mitochondrial function in this disease. Treatment with the fusion proteins enhanced cell viability and most importantly reduced MMA levels. Treatment also enhanced albumin and urea secretion in a CRISPR/Cas9-engineered HepG2 MUT (-/-) liver cell line. Therefore, we suggest using this TAT-MTS-Protein approach for the treatment of MMA.


Isolating the influences of fluid dynamics on selectin-mediated particle rolling at venular junctional regions.
The objective of this study was to isolate the impact of hydrodynamics on selectin-mediated cell rolling in branched microvessels. Significant advancements have been made in furthering the understanding of complex interactions between biochemical and physical factors in the inflammatory cascade in simplified planar geometries. However, few studies have sought to quantify the effects of branched configurations and to isolate the effects of associated fluid forces. Experimental techniques were developed to perform in vitro adhesion experiments in Y-shaped micro-slides. The micro-slides were coated with P-selectin and microspheres coated with Sialyl-Lewisx were observed as they rolled in the chambers at different wall shear stresses. Study results revealed that microsphere rolling velocities and rolling flux were lowest in regions closest to the apex of a junctional region and were dependent on both branch angle and wall shear stress. The regions closest to the junctional region were shown to have low bulk flow velocities and shear stresses using computational fluid dynamics (CFD) modeling. Collectively, the study demonstrates that despite the presence of a uniform coating of P-selectin, hydrodynamic factors associated with the chamber geometry yield non-uniform effects on particle behavior. These findings could explain why cells have been observed to preferentially adhere or transmigrate near junctional regions. Future characterization of inflammatory processes in microvascular network configurations is therefore crucial for furthering our fundamental understanding of inflammation.


Teaching empathy and other compassion-based communication skills.
Empathy plays an important role in comprehensive nursing care. Empathy outcome research shows that exposure to an empathetic person has a palliative and even healing effect on patients. Teaching nurses how to communicate with empathy is crucial to unleash the true potential that empathy has to transform and heal. Four active listening skills and six compassion-based skills are defined. A suggested training rubric appropriate for use in multiple training contexts is provided.


Fourier transform infrared spectroscopy study of ligand photodissociation and migration in inducible nitric oxide synthase.
Inducible nitric oxide synthase (iNOS) is a homodimeric heme enzyme that catalyzes the formation of nitric oxide (NO) from dioxygen and L-arginine (L-Arg) in a two-step process. The produced NO can either diffuse out of the heme pocket into the surroundings or it can rebind to the heme iron and inhibit enzyme action. Here we have employed Fourier transform infrared (FTIR) photolysis difference spectroscopy at cryogenic temperatures, using the carbon monoxide (CO) and NO stretching bands as local probes of the active site of iNOS. Characteristic changes were observed in the spectra of the heme-bound ligands upon binding of the cofactors. Unlike photolyzed CO, which becomes trapped in well-defined orientations, as indicated by sharp photoproduct bands, photoproduct bands of NO photodissociated from the ferric heme iron were not visible, indicating that NO does not reside in the protein interior in a well-defined location or orientation. This may be favorable for NO release from the enzyme during catalysis because it reduces self-inhibition. Moreover, we used temperature derivative spectroscopy (TDS) with FTIR monitoring to explore the dynamics of NO and carbon monoxide (CO) inside iNOS after photodissociation at cryogenic temperatures. Only a single kinetic photoproduct state was revealed, but no secondary docking sites as in hemoglobins. Interestingly, we observed that intense illumination of six-coordinate ferrous iNOS oxy-NO ruptures the bond between the heme iron and the proximal thiolate to yield five-coordinate ferric iNOS oxy-NO, demonstrating the strong trans effect of the heme-bound NO.


Development of a Research Agenda Focused on Academic Health Departments.
An academic health department (AHD) is a formal partnership between an academic institution and a governmental public health agency. Case studies have described the value of individual AHDs in the areas of student engagement, practice-based research, workforce development, and service. With growing interest in AHDs and the increasing importance of academic-practice linkages in both academic programs' and public health agencies' accreditation processes, articulating a research agenda focused on the AHD model can be useful for stimulating the research and practice fields to further develop the evidence base for AHDs. We provide a research agenda, developed through an iterative process involving academicians, practitioners, and others interested in academic-practice linkages.


Expanding Faculty Development of Teaching Skills: A National Needs Assessment of Pediatric Critical Care Medicine Faculty.
High-quality clinical teaching is an essential element in preparing trainees to become independently competent clinicians. In order to better understand the context-specific faculty development needs of teaching faculty in a specific community, we sought to determine the self-reported teaching skill deficits of pediatric critical care medicine faculty and their preferences and motivations regarding faculty development to enhance their teaching. Modified Delphi technique was used to create an online survey in which respondents rated their need for education on a variety of teaching skills, their preferred learning modalities, and factors that motivate their participation in faculty development. Pediatric Critical Care Medicine divisions at the 64 sites in the United States with fellowship programs. Five-hundred forty-five Pediatric Critical Care Medicine faculty who teach fellows and other trainees. None. Response rate was 40%. Respondents reported a median of 8.5 years (interquartile range, 4-16 yr) as teaching faculty. The median age of faculty was 44.6 years (interquartile range, 38-50 yr). Only 20% of respondents indicated that improving their teaching was a low priority. Thirty-six percent of respondents had not participated in any formal teaching skill development as faculty. The most frequently cited factors motivating engagement in faculty development were education being included as part of regularly attended conferences, resources readily available when needed, and participation promoted by a supervisor. Preferred learning modalities included a brief discussion with a colleague, a 10-minute video, and a regular conference series. Pediatric Critical Care Medicine faculty reported they experience challenges in teaching and would benefit from faculty development training aimed at improving their knowledge and skills about being an educator. Preferred learning methods and motivating factors highlight the importance of efficiency in content delivery and endorsement by faculty supervisors. Consideration of these needs and preferences may be useful in creating context-focused, community of practice-based faculty development programs.


Keratolimbal allograft.
Keratolimbal allograft (KLAL) transplants limbal tissue attached to a corneoscleral carrier from a cadaveric donor to deliver a large number of stem cells to the recipient. The present article will provide a review of KLAL focusing on the recent literature. Recent findings pertain to tissue selection, immunosuppression and adverse event profiles, and postoperative complications (particularly related to immunologic rejection). KLAL permits the treatment of limbal stem cell deficiency eyes when there is no available living-related or autograft tissue with minimal risk of irreversible toxicity from modern systemic immunosuppression. The prevention of immunologic graft rejection with the use of systemic immunosuppression after KLAL is critical and may require extending systemic immunosuppression treatment longer than previously thought. With vigilant postoperative management, KLAL can allow successful treatment of the most severely diseased eyes.


Clinical tumour size and prognosis in lung cancer. Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S).
In the staging of lung cancer (LC), tumour size is a variable that can be used to separate primary tumour, regional nodes, metastasis (TNM), stages T1 and T2 (<3 or >3 cm). The objective of this study was to evaluate the prognostic value of tumour size before thoracotomy and to determine whether tumour size can be used to classify LC as T3. This multi-institutional cooperative longitudinal prospective study in Spanish hospitals located throughout the country, with a broad range of activity levels, included all consecutive cases of LC treated surgically from October 1993 to September 1996 (n=2,361). Four prognostic groups, characterized by tumour size, were identified according to the Schoenfeld procedure: a) 0-2 cm (n=173); b) 2.1-4 cm (n=542); c) 4.1-7 cm (n= 413); and d) >7 cm (n=77). The 2-yr survival rates by group were a=0.78 (95% confidence interval (CI) 0.71-0.84); b=0.67 (95% CI 0.62-0.71); c=0.58 (95% CI 0.53-0.63); d=0.41 (95% CI 0.29-0.52). The log-rank comparisons of the survival curves were significant for the four groups (a versus b=0.0008, b versus c=0.003, c versus d=0.016). The clinical tumour size of lung cancer defined four prognostic groups (0-2 cm, 2.1-4 cm, 4.1-7 cm; and >7 cm). Lung cancer with a diameter >7 cm had a prognosis similar to that of stage T3 or stage IIB.


Evolution of Young Sex Chromosomes in Two Dioecious Sister Plant Species with Distinct Sex Determination Systems.
In the last decade, progress has been made in methods to identify the sex determination system in plants. This gives the opportunity to study sex chromosomes that arose independently at different phylogenetic scales, and thus allows the discovery and the understanding of early stages of sex chromosome evolution. In the genus Silene, sex chromosomes have evolved independently in at least two clades from a nondioecious ancestor, the Melandrium and Otites sections. In the latter, sex chromosomes could be younger than in the section Melandrium, based on phylogenetic studies and as no heteromorphic sex chromosomes have been detected. This section might also exhibit lability in sex determination, because male heterogamy and female heterogamy have been suggested to occur.In this study, we investigated the sex determination system of two dioecious species in the section Otites (Silene otites and its close relative Silene pseudotites). Applying the new probabilistic method SEX-DETector on RNA-seq data from cross-controlled progenies, we inferred their most likely sex determination system and a list of putative autosomal and sex-linked contigs. We showed that the two phylogenetically close species differed in their sex determination system (XY versus ZW) with sex chromosomes that derived from two different pairs of autosomes. We built a genetic map of the sex chromosomes and showed that both pairs exhibited a large region with lack of recombination. However, the sex-limited chromosomes exhibited no strong degeneration. Finally, using the "ancestral" autosomal expression of sex-linked orthologs of nondioecious S. nutans, we found a slight signature of dosage compensation in the heterogametic females of S. otites.


[Recording of azimuthal characteristics of the polarized fluorescence of microstructures using a semi-wave plate].
We have suggested and grounded theoretically application of lambda/2 plate for the registration azimuth characteristics (AC) of polarized fluorescence of microstructures. Proper device of polarization microfluorimeter has been worked out. Application of this device in case of transmitted light illumination has allowed to record AC of a very small objects (up to 1 mkm) and add to a-curacity of measurements. In the case of incident light illumination one need to make achromatic lambda/2 plates.


Characterization of CbCyp51 from field isolates of Cercospora beticola.
The hemibiotrophic fungus Cercospora beticola causes leaf spot of sugar beet. Leaf spot control measures include the application of sterol demethylation inhibitor (DMI) fungicides. However, reduced sensitivity to DMIs has been reported recently in the Red River Valley sugar beet-growing region of North Dakota and Minnesota. Here, we report the cloning and molecular characterization of CbCyp51, which encodes the DMI target enzyme sterol P450 14α-demethylase in C. beticola. CbCyp51 is a 1,632-bp intron-free gene with obvious homology to other fungal Cyp51 genes and is present as a single copy in the C. beticola genome. Five nucleotide haplotypes were identified which encoded three amino acid sequences. Protein variant 1 composed 79% of the sequenced isolates, followed by protein variant 2 that composed 18% of the sequences and a single isolate representative of protein variant 3. Because resistance to DMIs can be related to polymorphism in promoter or coding sequences, sequence diversity was assessed by sequencing >2,440 nucleotides encompassing CbCyp51 coding and flanking regions from isolates with varying EC(50) values (effective concentration to reduce growth by 50%) to DMI fungicides. However, no mutations or haplotypes were associated with DMI resistance or sensitivity. No evidence for alternative splicing or differential methylation of CbCyp51 was found that might explain reduced sensitivity to DMIs. However, CbCyp51 was overexpressed in isolates with high EC(50) values compared with isolates with low EC(50) values. After exposure to tetraconazole, isolates with high EC(50) values responded with further induction of CbCyp51, with a positive correlation of CbCyp51 expression and tetraconazole concentration up to 2.5 μg ml(-1).


Comparison of Markov versus quantum dynamical models of human decision making.
What kind of dynamic decision process do humans use to make decisions? In this article, two different types of processes are reviewed and compared: Markov and quantum. Markov processes are based on the idea that at any given point in time a decision maker has a definite and specific level of support for available choice alternatives, and the dynamic decision process is represented by a single trajectory that traces out a path across time. When a response is requested, a person's decision or judgment is generated from the current location along the trajectory. By contrast, quantum processes are founded on the idea that a person's state can be represented by a superposition over different degrees of support for available choice options, and that the dynamics of this state form a wave moving across levels of support over time. When a response is requested, a decision or judgment is constructed out of the superposition by "actualizing" a specific degree or range of degrees of support to create a definite state. The purpose of this article is to introduce these two contrasting theories, review empirical studies comparing the two theories, and identify conditions that determine when each theory is more accurate and useful than the other. This article is categorized under: Economics > Individual Decision-Making Psychology > Reasoning and Decision Making Psychology > Theory and Methods.


Effect of Emotional Labor and Stress on Premenstrual Syndrome among Hospital Nurses.
This study is an explorative survey to examine emotional labor, stress, and premenstrual syndrome among hospital nurses and to examine relationships among them. Data were collected from 228 nurses working at hospitals using structured questionnaires from September to October, 2014. Data were analyzed using SPSS 21.0 by frequency, descriptive statistics, t-test, one-way ANOVA, and Pearson's correlation coefficient. Score of emotional labor was different by work time per week (F=4.03, p=.019), and menstrual amount (F=5.18, p=.006). Level of stress was different by marital status (t=2.29, p=.023), pattern of work (t=-3.63, p<.001), work time per week (F=3.39, p=.035), regularity of menstrual cycle (t=-4.20, p<.001), and exercise frequency (F=4.28, p=.015). Scores of premenstrual syndrome were different by regularity of menstrual cycle (t=-3.18, p=.002), and menstrual amount (F=5.88, p=.003). Emotional labor was related with perceived stress (r=.40, p<.001) and premenstrual syndrome (r=.23, p<.001). Also, perceived stress was related with premenstrual syndrome (r=.33, p<.001). Nurses' emotional labor, stress, and premenstrual syndrome were higher than the average. Emotional labor was correlated with stress and premenstrual syndrome, premenstrual syndrome with stress. This study shows that it is necessary to understand these relationships and to search for nursing intervention to ease emotional labor, stress, and premenstrual syndrome.


Isolation and characterization of a cDNA encoding a CBF transcription factor from E. globulus.
The transcription factors CBF/DREB play an important role during low temperature, drought and high-salt stress in higher plants. In this work, we isolated one full-length CBF cDNA clone from the angiosperm Eucalyptus globulus. The derived peptide sequence reveals that it encodes a transcriptional activator that has all the characteristic motifs present in CBF proteins previously described in Arabidopsis and tomato. RT-PCR analysis shows that EgCBF1 is transiently induced in E. globulus seedlings that had been exposed to low temperature within the first 15 min. These results suggest that the isolated CBF gene participates in the cold responsive pathway of E. globulus.


Bisindeno-annulated pentacenes with exceptionally high photo-stability and ordered molecular packing: simple synthesis by a regio-selective Scholl reaction.
Bisindeno-annulated pentacenes 3a and 3b were synthesized by a simple regio-selective, FeCl3-mediated Scholl reaction from the corresponding 6,13-diaryl pentacene precursors. The fusion of two indeno-units dramatically changes the electronic properties and chemical reactivity of pentacene and the obtained compounds exhibited exceptionally high photo-stability in the solution, with a half-life time of 11.2 (3a) and 32.0 (3b) days under ambient light and air conditions. Ordered molecular packing with a small π-π stacking distance was observed in the single crystals of 3a and 3b. Our research provides a promising strategy to access stable higher order acenes with controlled molecular order.


The dual role of palladium in enhancing the photocatalytic activity of CdS dispersed on NaY-zeolite.
A stable photocatalyst, CdS dispersed on zeolite with Pd as both the dopant and the co-catalyst, has been developed. Enhancement of photocatalytic activity for hydrogen generation is observed for CdS when doped with palladium and dispersed on NaY-zeolite (CdPdS-Z). A further increase in the photocatalytic activity of CdPdS-Z is observed when palladium is added as a co-catalyst (Pd-CdPdS-Z). Cd0.95Pd0.05S-Z is synthesized via a facile soft chemical route and the Pd co-catalyst is loaded onto the composite using a wet impregnation method. This composite catalyst exists as two phases consisting of CdPdS and zeolite and CdPdS exists as a highly dispersed phase on zeolite as revealed by TEM studies. The Pd doped CdS-zeolite composite exhibits increased visible light absorption indicating the alteration of the band structure of CdS as a result of doping. Time resolved fluorescence studies reveal that the lifetime of the charge carriers is higher in the composites than in pure CdS. A detailed characterization using XRD, Raman and X-ray photoelectron spectroscopy indicates that Pd has substituted for Cd in the CdS lattice and Pd exists in the Pd(2+) oxidation state. Solid state MAS NMR studies indicate that an interaction exists between CdS (or CdPdS) and zeolite at the interface and Cd selectively interacts with Al of the zeolite framework. The photocatalytic activity of the Pd-CdPdS-Z catalyst remains unchanged with repeated cycles. Characterization of the used catalyst indicates that it is stable under the present experimental conditions. The enhanced photocatalytic activity of Pd-CdPdS-Z is attributed to the enhanced visible light absorption arising due to Pd doping and increased lifetime of the photogenerated charge carriers assisted by zeolite and the Pd co-catalyst. This study highlights the multiple roles played by palladium in enhancing the photocatalytic activity of the CdS-zeolite composite.


Social-economical decision making in current and remitted major depression.
Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown. In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms. We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05). Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision-making abnormalities in depression.


A diagnostic approach to confirm Mycoplasma hyopneumoniae "Day zero" for pathogen eradication.
Breeding herds in the US are trending toward eradication of Mycoplasma hyopneumoniae (M. hyopneumoniae) due to the positive impact on welfare and downstream production. In an eradication program, "Day 0″ is the time point when the last replacement gilts to enter the herd were exposed to M. hyopneumoniae and marks the beginning of a herd closure. However, no specific diagnostic protocols are available for confirmation of successful exposure to define Day 0. Therefore, the objective of this study was to develop diagnostic guidelines, including sample collection approaches, for two common gilt exposure methods to confirm an entire population has been infected with M. hyopneumoniae following purposeful exposure. Forty gilts, age 21-56 days, were ear-tagged for longitudinal sample collection at five commercial gilt developer units (GDUs) and were exposed to M. hyopneumoniae by natural contact or aerosolization. Study gilts originated from sources known to be negative to major swine pathogens, including M. hyopneumoniae, and were sampled prior to exposure to confirm negative status, then every two weeks. Blood samples were collected for antibody detection, while laryngeal and deep tracheal secretions and pen based oral fluids were collected for PCR, and sampling continued until at least 85% of samples were positive by PCR. Detection of M. hyopneumoniae varied greatly based on sample type. Oral fluids showed the lowest detection in groups of gilts detected positive by other sample types. Detection by PCR in deep tracheal secretions was higher than in laryngeal secretions. Seroconversion to and PCR detection of M. hyopneumoniae on oral fluids were delayed compared to PCR detection at the individual level. By two weeks post-exposure, at least 85% of study gilts in three GDUs exposed by aerosolization were PCR positive in deep tracheal secretions. Natural contact exposure resulted in 22.5% of study gilts becoming PCR positive by two weeks post-initial exposure, 61.5% at four weeks, and 100% at six weeks on deep tracheal secretions. Deep tracheal secretions required the lowest number of gilts to sample for the earliest detection compared to all other samples evaluated. As observed in one of the GDUs using aerosolization, demonstration of failure to expose gilts to M. hyopneumoniae allowed for early intervention in the exposure protocol and delay of Day 0, for accurate timing of the eradication protocol. Sampling guidelines proposed in this study can be used for verification of M. hyopneumoniae infection of gilts following exposure to determine Day 0 of herd closure.


[Enzyme immobilization via silochromes, modified by transition metal salts].
The immobilization of pectoawamorine G 10X, pronase E and P, protease from Bac. mesentericus and rat liver microsomal fraction was performed by sylochromes modified by Ti, Zr and Hf salts. The pectinesterase, caseinolytic, esterase and hydroxylating activity of the immobilized preparations, their stability during storage, thermostability and pH optimum are determined. Of greatest interest for practical application are preparations of pectoawamorine. G 10X and pronase E and P immobilized by HfOCl2.


Is there any change of stroke incidence during Ramadan?
Ramadan is a special month for Muslims, as fasting during Ramadan is a religious duty. In this study we investigated whether stroke incidence differs during Ramadan compared to other months. All patients with stroke admitted to any hospital in the Isparta Province between 1991-1995 were included in this study. Patients were divided into 2 groups according to the month of onset of stroke. The first group included patients with strokes that occurred in Ramadan and the second group strokes with onset in other months. The stroke incidence of Isparta has been found to be 137 per 100,000 for people older than 25 years. There were no statistically significant differences between the age and sex distribution of patients and the incidences of strokes in both groups. We concluded that fasting during Ramadan has no affect on stroke occurrence in the Isparta Province.


[Rehabilitation of children with external intestinal fistula].
Experience in the treatment of 153 children with external intestinal fistulas is discussed. In 6 children the intestinal fistulas occurred as the result of a pyodestructive process in the abdominal cavity, in 147 children they were formed for therapeutic purposes. The choice of the method of treatment is individual and is determined by the character of the fistula. A magneto-++-compressive inter-intestinal++ anastomosis (MCIA) was formed for exclusion of the intestinal fistulas. Under conditions of peritonitis in gun-barrel enterostomy intraoperative formation of the MCIA can be undertaken. The method was applied in 21 children, no complications occurred. In closure of gun-barrel enterostomy an operative method was elaborated with preservation of the greater part of the magneto-++-compressive anastomosis.


Consolidating CCDs from multiple data sources: a modular approach.
Healthcare providers sometimes receive multiple continuity of care documents (CCDs) for a single patient encompassing the patient's various encounters and medical history recorded in different information systems. It is cumbersome for providers to explore different pages of CCDs to find specific data which can be duplicated or even conflicted. This study describes initial steps toward a modular system that integrates and de-duplicates multiple CCDs into one consolidated document for viewing or processing patient-level data. The authors developed a prototype system to consolidate and de-duplicate CCDs. The system is engineered to be scalable, extensible, and open source. Using a corpus of 150 de-identified CCDs synthetically generated from a single data source with a common vocabulary to represent 50 unique patients, the authors tested the system's performance and output. Performance was measured based on document throughput and reduction in file size and volume of data. The authors further compared the output of the system with manual consolidation and de-duplication. Testing across multiple vendor systems or implementations was not performed. All of the input CCDs was successfully consolidated, and no data were lost. De-duplication significantly reduced the number of entries in different sections (49% in Problems, 60.6% in Medications, and 79% in Allergies) and reduced the size of the documents (57.5%) as well as the number of lines in each document (58%). The system executed at a rate of approximately 0.009-0.03 s per rule depending on the complexity of the rule. Given increasing adoption and use of health information exchange (HIE) to share data and information across the care continuum, duplication of information is inevitable. A novel system designed to support automated consolidation and de-duplication of information across clinical documents as they are exchanged shows promise. Future work is needed to expand the capabilities of the system and further test it using heterogeneous vocabularies across multiple HIE scenarios.


The causes and prevention of stroke associated with carotid artery surgery.
Four hundred eighty-eight consecutive carotid endarterectomies were performed on 417 patients. Stroke, as a procedure-related complication, occurred in 12 patients, or 2.4 per cent of cases. Five causes of operative or postoperative stroke were identified: 1) operative embolization, 2) postoperative hypertensive episodes with cerebral hemorrhage, 3) technical error, 4) conversion of ischemic infarct to hemorrhagic infarct, and 5) clamp-time ischemia. The use of several modalities evolved as routine in an effort to reduce mortality and morbidity: 1) minimal manipulation of the artery until after cross clamping to prevent microembolization; 2) routine direct arterial blood pressure monitoring and control during and after surgery; 3) routine operative arteriography to detect and correct technical errors at the time of surgery; 4) liberal use of CAT scans preoperatively to avoid surgery on patients with small, unrecognized infarcts; and 5) stump pressure measurement and selective shunting to prevent ischemia during the endarterectomy. The anatomical-pathological combination of a high bifurcation and high plaque is identified as a high-risk situation.


Enhancement of antibody responses by DNA immunization using expression vectors mediating efficient antigen secretion.
The immune responses elicited in mice, after intradermal (i.d.) immunization with plasmids encoding secreted or intracellular forms of HIV-1 nef, HIV-1 tat or C. pneumoniae omp2 proteins, respectively, were compared. To mediate secretion of these proteins the genes were fused to a heterologous signal sequence from murine heavy chain IgG. The nef- and omp2-specific antibody responses were dramatically increased when mice were inoculated with the plasmid encoding the secreted form of these proteins. In contrast, HIV-1 tat comprising an internal strong nuclear targeting sequence could not be induced to secretion and subsequently no enhanced antibody response was observed. Slight improvement of the HIV-1 nef antibody response was achieved after co-inoculation with a granulocyte-macrophage colony-stimulating factor (GM-CSF) expression vector. Further, nef-specific T-cell responses were induced after nef DNA injections, and were of Th1-like phenotype regardless of whether the nef protein was secreted or not. The system described in this study, using a plasmid vector with a strong heterologous signal sequence that mediate efficient antigen secretion in vivo, may have wide applicability for the induction of high antibody levels to normally non-secreted antigens.


Evidence-based medicine - are we boiling the frog?
Evidence-based medicine has been defined as 'The conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.' There are two major assumptions in this statement. First, it is assumed that the evidence is in fact the best. Unfortunately this is not necessarily so, and published evidence is affected by bias, sponsorship, and blind faith in mathematical probability which may not be clinically relevant. Second, the evidence is population based and may not be applicable to the individual, and blind adherence to this concept may cause harm. We must not abandon clinical experience and judgement in favour of a series of inanimate data points. Medicine is an uncertain science.


Detecting human papillomavirus in ocular surface diseases.
Human papillomavirus (HPV) infection has been implicated as a possible inducing factor for benign and neoplastic ocular surface diseases such as pterygia and ocular-surface squamous neoplasia (OSSN). However, the wide range in HPV prevalence previously reported for both diseases adds controversy to, and highlights the limitations of, this field. The aim of this study was to determine the prevalence of HPV in pterygia and OSSN and to devise a standardized approach for detecting viral DNA in ocular tissue samples. DNA was extracted from a variety of specimens (n = 160), including formalin-fixed paraffin-embedded tissue shavings, fresh tissue, and cultured cells. Nested PCR for HPV with consensus and subtype-specific primers was used to detect viral DNA. Confirmatory assays, including molecular sequencing, histology, and immunohistochemistry for HPV E6 protein and p16 were also performed. HPV was not detected in pterygia or normal conjunctiva. However, 6.5% (3/46) of OSSN samples were HPV-positive by PCR, sequencing, and immunohistochemistry. Positive cases were all squamous cell carcinoma of the conjunctiva (SCCC), the most severe form of OSSN, representing 12.5% (3/24) of SCCCs in our cohort. HPV-16 was the genotype identified in each case and this correlated with the presence of koilocytes and intense immunoreactivity for p16. Our study found no association between pterygia and OSSN with other oncogenic viruses, such as EBV or CMV, as they were just as prevalent in normal conjunctiva. The low prevalence of HPV-16 in ocular surface disease suggests infection is not a cause but a cofactor in disease development.


Blueberry and malvidin inhibit cell cycle progression and induce mitochondrial-mediated apoptosis by abrogating the JAK/STAT-3 signalling pathway.
Blueberries, a rich source of anthocyanins have attracted considerable attention as functional foods that confer immense health benefits including anticancer properties. Herein, we assessed the potential of blueberry and its major constituent malvidin to target STAT-3, a potentially druggable oncogenic transcription factor with high therapeutic index. We demonstrate that blueberry abrogates the JAK/STAT-3 pathway and modulates downstream targets that influence cell proliferation and apoptosis in a hamster model of oral oncogenesis. Further, we provide mechanistic evidence that blueberry and malvidin function as STAT-3 inhibitors in the oral cancer cell line SCC131. Blueberry and malvidin suppressed STAT-3 phosphorylation and nuclear translocation thereby inducing cell cycle arrest and mitochondrial-mediated apoptosis. However, the combination of blueberry and malvidin with the STAT-3 inhibitor S3I-201 was more efficacious in STAT-3 inhibition relative to single agents. The present study has provided leads for the development of novel combinations of compounds that can serve as inhibitors of STAT-mediated oncogenic signalling.


Pancreatoduodenectomy with Venous Resection or Palliative Therapy? A Meta-Analysis.
This review evaluated the risks and survival benefits of pancreatoduodenectomy associated with venous resection compared with palliative surgery. A systematic review with meta-analysis was performed. Higher overall survival was observed in the pancreatic resection group (HR = 4.000; 95% CI 2.800 to 5.200). However, the palliative group had fewer complications (RD = -0.170; 95% CI -0.260 to -0.070). There was no significant difference in the mortality rates (RD = 0.000; 95% CI -0.030 to 0.030). In centres with experience in pancreatic surgery, resection may be considered for locally advanced cancer and major venous invasion. Pancreaticoduodenectomy with vascular resection may improve survival for periampullary tumours compared with palliation therapy. However, pancreaticoduodenectomy with major venous resection has potentially higher morbidity than palliation therapy. Key Words: Pancreatoduodenectomy, Pancreatic neoplasms, Vascular surgical procedures.


MMP-9 gene variants increase the risk for non-atopic asthma in children.
Atopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in BAL samples of young children with wheezing. Both neutrophils as well as eosinophils may secrete matrix metalloproteinase 9 (MMP-9). Considering that MMP-9 plays an important role in airway wall thickening and airway inflammation, it may influence the development of obstructive airway phenotypes in children. In the present study we investigated whether genetic variations in MMP-9 influence the development of different forms of childhood asthma. Genotyping of four HapMap derived tagging SNPs in the MMP-9 gene was performed using MALDI-TOF MS in three cross sectional study populations of German children (age 9-11; N = 4,264) phenotyped for asthma and atopic diseases according to ISAAC standard procedures. Effects of single SNPs and haplotypes were studied using SAS 9.1.3 and Haploview. SNP rs2664538 significantly increased the risk for non-atopic wheezing (OR 2.12, 95%CI 1.40-3.21, p < 0.001) and non-atopic asthma (OR 1.66, 95%CI 1.12-2.46, p = 0.011). Furthermore, the minor allele of rs3918241 may be associated with decreased expiratory flow measurements in non-atopic children. No significant effects on the development of atopy or total serum IgE levels were observed. Our results have shown that homozygocity for MMP-9 variants increase the risk to develop non-atopic forms of asthma and wheezing, which may be explained by a functional role of MMP-9 in airway remodeling. These results suggest that different wheezing disorders in childhood are affected differently by genetic alterations.


Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study.
To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen (STR) for the initial treatment of HIV-1 infection. Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks. Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (<50 HIV copies per milliliter) at week 24 (86.6%; 89.7%) and at week 48 (88.4%; 87.9%), and had similar improvements in CD4 at week 48 (177; 204), respectively. Both treatments were well tolerated, and most adverse events were self-limiting and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on E/C/F/TAF had smaller reductions in estimated creatinine clearance (-5.5 vs. -10.1 mL/min, P = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral density for hip (-0.62% vs. -2.39%, P < 0.001) and spine (-1.00% vs. -3.37%, P < 0.001). Patients on E/C/F/TAF had higher increases in total cholesterol, low-density lipoprotein, and high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density.


Chain pullout and mobility effects in friction and lubrication.
The interfacial shear stress that occurs when a network of a polymer that is highly mobile at the segment level (an elastomer) is slid over a smooth surface of an immobile (glassy) polymer has been measured. The glassy material is covered by a thin layer of end-attached chains of the mobile material. The experiment was designed so that there were no free chains at the interface; the slip occurred between network chains on the one side and rigid material plus end-attached mobile chains on the other side. Two main results were obtained. (i) The interfacial shear stress is strongly affected by the segment mobility of the materials on both sides of the slip plane, and considerably lower stress is observed when the materials on both sides of the interface are highly mobile. (ii) Very thin layers of tethered chains can increase the interfacial friction. Both results are relevant to the understanding of a number of practical situations that range from the operation of thin layers of lubricants, such as those found in magnetic storage devices, to the problem of wall slip and melt fracture in polymer processing.


[Central hemodynamics in chronic alcoholics].
Central hemodynamics were assessed in 86 chronic alcoholic patients in relation to the stage of the disease and the kind of alcoholic dependence. The values of major hemodynamic parameters were shown to depend on both the stage of the disease, and clinical manifestations of abstinence. The abstinence syndrome developing after a 3-5-day abstinence is associated with a gradual transition from eukinetic- to hypokinetic-type circulation, as the disease progresses. Hemodynamic shifts following recovery from acute delirium tremens are not related to the stage of the disease, and tend to hypokinetic-type circulation. During remission, hemodynamic parameters approach those of normal subjects.


The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation.
Circadian rhythms are daily physiological oscillations driven by the circadian clock: a 24-hour transcriptional timekeeper that regulates hormones, inflammation, and metabolism. Circadian rhythms are known to be important for health, but whether their loss contributes to colorectal cancer is not known. We tested the nonredundant clock gene Bmal1 in intestinal homeostasis and tumorigenesis, using the Apcmin model of colorectal cancer. Bmal1 mutant, epithelium-conditional Bmal1 mutant, and photoperiod (day/night cycle) disrupted mice bearing the Apcmin allele were assessed for tumorigenesis. Tumors and normal nontransformed tissue were characterized. Intestinal organoids were assessed for circadian transcription rhythms by RNA sequencing, and in vivo and organoid assays were used to test Bmal1-dependent proliferation and self-renewal. Loss of Bmal1 or circadian photoperiod increases tumor initiation. In the intestinal epithelium the clock regulates transcripts involved in regeneration and intestinal stem cell signaling. Tumors have no self-autonomous clock function and only weak clock function in vivo. Apcmin clock-disrupted tumors show high Yes-associated protein 1 (Hippo signaling) activity but show low Wnt (Wingless and Int-1) activity. Intestinal organoid assays show that loss of Bmal1 increases self-renewal in a Yes-associated protein 1-dependent manner. Bmal1 regulates intestinal stem cell pathways, including Hippo signaling, and the loss of circadian rhythms potentiates tumor initiation. Transcript profiling: GEO accession number: GSE157357.


Incidence of Travelers' Diarrhea among Adult Foreign Travelers in Thailand: A Prospective Study.
Travelers' diarrhea (TD) is common among foreign travelers to Thailand. We performed a prospective cohort study to determine the TD incidence among foreign adult travelers to Thailand. We retrieved baseline demographic data, travel plans, and health history on enrolling individuals and collected follow-up questionnaires on days 7, 14, and 28 from the day of arrival. We analyzed data from 349 eligible participants. The mean participants' age was 32.3 years; 55.4% were men. Most of the participants had visited a travel clinic for vaccinations and counseling after arrival in Thailand. The cumulative incidences of the participants developing TD were 14.0% (49/349), 23.5% (82/349), and 33.0% (115/349) at 7, 14, and 28 days, respectively. The median time to develop TD was 9 days (interquartile range 5-18 days) post-arrival. Of 115 participants with TD, 64.3% (74/115) consulted a physician, 1.7% (2/115) were hospitalized, and 11.3% (13/115) had to change their travel plans. We identified young age, eating street food, and not routinely washing hands after using a toilet as risk factors significantly associated with the incidence of TD using the log-rank test in our survival analysis. Up to one-third of foreign travelers developed diarrhea during the first month, and some cases were severe. Although no highly effective TD prevention method exists, the practice of good personal hygiene and avoidance of food and drinks derived from unsanitary sources are still recommended to reduce the risk of travelers' TD.


A Plant Immune Receptor Adopts a Two-Step Recognition Mechanism to Enhance Viral Effector Perception.
Plant intracellular nucleotide binding leucine-rich repeat (NLR) immune receptors play critical roles in pathogen surveillance. Most plant NLRs characterized so far were found to use a single domain/sensor to recognize pathogen effectors. Here we report that the Sw-5b NLR immune receptor uses two distinct domains to detect the viral movement protein NSm encoded by tospovirus. In addition to its leucine-rich repeat (LRR) domain that has been previously reported, the N-terminal Solanaceae domain (SD) of Sw-5b also interacts with NSm and a conserved 21-amino-acid region of NSm (NSm21). The specific interaction between Sw-5b SD and NSm is required for releasing the inhibitory effect of coiled-coil domain on the NB-ARC-LRR region. Furthermore, we found that the binding of NSm affects the nucleotide binding activity of the NB-ARC-LRR in vitro, while Sw-5b NB-ARC-LRR is activated only when NSm and NSm21 levels are high. Interestingly, Sw-5b SD could significantly enhance the ability of the NB-ARC-LRR to detect low levels of NSm effector and facilitate its activation and induction of defense response. An Sw-5b SD mutant that is disrupted in NSm recognition failed to enhance the ability of the NB-ARC-LRR to sense low levels of NSm and NSm21. Taken together, our results suggest that Sw-5b SD functions as an extra sensor and the NB-ARC-LRR as an activator, and that Sw-5b NLR adopts a two-step recognition mechanism to enhance viral effector perception.


Psychiatric diagnosis and psychological symptoms in impotence.
A sample of 137 males who presented with a principal complaint of impotence were assessed regarding manifest psychopathology through DSM-III psychiatric diagnosis and the SCL-90-R, a self-report symptom inventory. Contrasts in self-reported symptoms among dysfunctional groups assigned different DSM-III diagnoses proved to be very significant, as were contrasts with patients free of current psychiatric diagnoses. When the sample was separated into the three groups of organic etiology, psychogenic etiology with psychiatric diagnosis, and psychogenic etiology without psychiatric diagnosis, few significant differences in group profiles were uncovered. Findings of the study lend strong support to the notion that males with erectile sexual dysfunction reveal disproportionate levels of psychological symptoms and psychopathology. The results failed to confirm the premise that biogenic versus psychogenic etiologies in impotence can be effectively identified solely on the basis of the psychological symptom picture.


Sales of Over-the-Counter Products Containing Codeine in 31 Countries, 2013-2019: A Retrospective Observational Study.
Opioid prescribing trends have been investigated in many countries. However, the patterns of over-the-counter purchases of opioids without a prescription, such as codeine combinations, are mostly unknown. We aimed to assess national sales and expenditure trends of over-the-counter codeine-containing products purchased in countries with available data over 6 years. We conducted a retrospective observational study using electronic point-of-sale data from the human data science company, IQVIA, for countries that had such data, including Argentina, Belgium, Brazil, Bulgaria, Canada, Croatia, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Japan, Latvia, Lithuania, Mexico, the Netherlands, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, Spain, Switzerland, Thailand, the UK, and the USA. We calculated annual mean sales (dosage units/1000 population) and public expenditure (£/1000 population) for each country between April 2013 and March 2019 and adjusted for data coverage reported by IQVIA. We quantified changes over time and the types of products sold. In total, 31.5 billion dosage units (adjusted: 42.8 billion dosage units) of codeine, costing £2.55 billion (adjusted: £3.68 billion), were sold over the counter in 31 countries between April 2013 and March 2019. Total adjusted sales increased by 11% (from 3911 dosage units/1000 population in 2013 to 4358 in 2019) and adjusted public expenditure increased by 72% (from £263/1000 in 2013 to £451/1000 in 2019). Sales were not equally distributed; South Africa sold the most (36 mean dosage units/person), followed by Ireland (30 mean dosage units/person), France (20 mean dosage units/person), the UK (17.2 mean dosage units/person), and Latvia (16.8 mean dosage units/person). Types of products (n = 569) and formulations (n = 12) sold varied. In many parts of the world, substantial numbers of people may be purchasing and consuming codeine in over-the-counter products. Clinicians should ask patients about their use of over-the-counter products, and public health measures are required to improve the collection of sales data and the safety of such products. STUDY PROTOCOL PRE-REGISTRATION: https://osf.io/ay4mc . The pre-print version of this work is available on medRxiv: https://doi.org/10.1101/2021.04.21.21255888 .


Reproductive behavior of stallions and mares: comparison of free-running and domestic in-hand breeding.
Based on observational studies comparing social organization and reproductive behavior of equids breeding under feral, semi-feral, and domestic conditions, a series of comparisons and findings on reproductive physiology and behavior are presented. Simple changes in management and handling of mares and stallions that can improve reproductive efficiency and fertility or that can overcome specific breeding problems are discussed.


Cost-effectiveness of a fixed combination of netupitant and palonosetron (NEPA) relative to aprepitant plus granisetron (APR + GRAN) for prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a trial-based analysis.
To assess, from a United States (US) perspective, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving highly emetogenic chemotherapy (HEC). We analyzed patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical trial of NEPA (n = 412) versus APR + GRAN (n = 416). Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty was addressed via multivariate probabilistic sensitivity analyses (PSA). Compared to APR + GRAN, NEPA resulted in a gain of 0.09 quality-adjusted life-days (QALDs) (4.04 vs 3.95; 95% CI -0.06 to 0.25) and a significant total per-patient cost reduction of $309 ($943 vs $1252; 95% CI $4-$626), due principally to $258 in lower medical costs of CINV-related events ($409 vs $668; 95% CI -$46 to $572) and $45 in lower study drug costs ($531 vs $577). In the PSA, NEPA resulted in lower costs and higher QALD in 86.5% of cases and cost ≤ $25,000 per quality-adjusted life-year gained in 97.8% of cases. This first-ever economic analysis using patient-level data from a phase 3 trial comparing neurokinin-1 receptor antagonist (NK1 RA) antiemetic regimens suggests that NEPA is highly cost-effective (and in fact cost-saving) versus an aprepitant-based regimen in post-HEC CINV prevention. Actual savings may be higher, as we focused only on the first chemotherapy cycle and omitted the impact of CINV-related chemotherapy discontinuation.


Structure of the 40S ribosomal subunit of Plasmodium falciparum by homology and de novo modeling.
Generation of three dimensional structures of macromolecules using in silico structural modeling technologies such as homology and de novo modeling has improved dramatically and increased the speed by which tertiary structures of organisms can be generated. This is especially the case if a homologous crystal structure is already available. High-resolution structures can be rapidly created using only their sequence information as input, a process that has the potential to increase the speed of scientific discovery. In this study, homology modeling and structure prediction tools such as RNA123 and SWISS-MODEL were used to generate the 40S ribosomal subunit from Plasmodium falciparum. This structure was modeled using the published crystal structure from Tetrahymena thermophila, a homologous eukaryote. In the absence of the Plasmodium falciparum 40S ribosomal crystal structure, the model accurately depicts a global topology, secondary and tertiary connections, and gives an overall root mean square deviation (RMSD) value of 3.9 Å relative to the template׳s crystal structure. Deviations are somewhat larger in areas with no homology between the templates. These results demonstrate that this approach has the power to identify motifs of interest in RNA and identify potential drug targets for macromolecules whose crystal structures are unknown. The results also show the utility of RNA homology modeling software for structure determination and lay the groundwork for applying this approach to larger and more complex eukaryotic ribosomes and other RNA-protein complexes. Structures generated from this study can be used in in silico screening experiments and lead to the determination of structures for targets/hit complexes.


Enzymatic shaving of the tegument surface of live schistosomes for proteomic analysis: a rational approach to select vaccine candidates.
The membrane-associated and membrane-spanning constituents of the Schistosoma mansoni tegument surface, the parasite's principal interface with the host bloodstream, have recently been characterized using proteomic techniques. Biotinylation of live worms using membrane-impermeant probes revealed that only a small subset of the proteins was accessible to the reagents. Their position within the multilayered architecture of the surface has not been ascertained. An enzymatic shaving approach on live worms has now been used to release the most accessible components, for analysis by MS/MS. Treatment with trypsin, or phosphatidylinositol-specific phospholipase C (PiPLC), only minimally impaired membrane integrity. PiPLC-enriched proteins were distinguished from those released in parasite vomitus or by handling damage, using isobaric tagging. Trypsin released five membrane proteins, Sm200, Sm25 and three annexins, plus host CD44 and the complement factors C3 and C4. Nutrient transporters and ion channels were absent from the trypsin fraction, suggesting a deeper location in the surface complex; surprisingly, two BAR-domain containing proteins were released. Seven parasite and two host proteins were enriched by PiPLC treatment, the vaccine candidate Sm29 being the most prominent along with two orthologues of human CD59, potentially inhibitors of complement fixation. The enzymes carbonic anhydrase and APD-ribosyl cyclase were also enriched, plus Sm200 and alkaline phosphatase. Host GPI-anchored proteins CD48 and CD90, suggest 'surface painting' during worm peregrination in the portal system. Our findings suggest that the membranocalyx secreted over the tegument surface is not the inert barrier previously proposed, some tegument proteins being externally accessible to enzymes and thus potentially located within it. Furthermore, the detection of C3 and C4 indicates that the complement cascade is initiated, while two CD59 orthologues suggest a potential mechanism for its inhibition. The detection of several host proteins is a testimonial to the acquisitive properties of the tegument surface. The exposed parasite proteins could represent novel vaccine candidates for combating this neglected disease.


Living on the edge: the role of geography and environment in structuring genetic variation in the southernmost populations of a tropical oak.
Understanding the factors determining genetic diversity and structure in peripheral populations is a long-standing goal of evolutionary biogeography, yet little empirical information is available for tropical species. In this study, we combine information from nuclear microsatellite markers and niche modelling to analyse the factors structuring genetic variation across the southernmost populations of the tropical oak Quercus segoviensis. First, we tested the hypothesis that genetic variability decreases with population isolation and increases with local habitat suitability and stability since the Last Glacial Maximum (LGM). Second, we employed a recently developed multiple matrix regression with randomisation (MMRR) approach to study the factors associated with genetic divergence among the studied populations and test the relative contribution of environmental and geographic isolation to contemporary patterns of genetic differentiation. We found that genetic diversity was negatively correlated with average genetic differentiation with other populations, indicating that isolation and limited gene flow have contributed to erode genetic variability in some populations. Considering the relatively small size of the study area (<120 km), analyses of genetic structure indicate a remarkable inter-population genetic differentiation. Environmental dissimilarity and differences in current and past climate niche suitability and their additive effects were not associated with genetic differentiation after controlling for geographic distance, indicating that local climate does not contribute to explain spatial patterns of genetic structure. Overall, our data indicate that geographic isolation, but not current or past climate, is the main factor determining contemporary patterns of genetic diversity and structure within the southernmost peripheral populations of this tropical oak.


Effect of a hands-free wire on specific absorption rate for a waist-mounted 1.8 GHz cellular telephone handset.
A common feature of cellular telephony is the use of a 'hands-free' audio extension lead connected to a waist-worn handset. Interaction between the transmitting antenna, the wire and the user's body can occur, with detrimental effects including polar pattern degradation, reduced efficiency and localized increases in specific absorption rate (SAR). Using a realistic full-body model of an adult male, finite difference time domain analysis was employed to investigate the coupling between a hip-mounted 1.8 GHz handset fitted with a monopole antenna and a 1 m long wire representing a hands-free wire. Conduction current densities were computed for three identifiable coupling modes: magnetic-only, conductive-only and combined conductive-and-magnetic. Magnetic-only coupling was dominant. Without the lead, placing the handset at waist height led to a 42.8% increase in the total energy deposited in the body, compared to use at the head. Introducing the lead further increased the body loss, with a reduction in system radiation efficiency from 52% to 43.7%. Without the hands-free lead, the peak 1 g and 10 g SARs were 0.450 W kg(-1) and 0.265 W kg(-1), respectively, for 125 mW transmit power. With the hands-free lead connected, these values increased to 1.14 W kg(-1) and 0.430 W kg(-1), respectively.


A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial.
Vitamin D deficiency leads to secondary hyperparathyroidism, increased bone turnover, and bone loss and, when severe, to osteomalacia. Vitamin D deficiency is common in elderly people, especially the institutionalized. The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D (25OHD), the main circulating metabolite. The international Multiple Outcomes of Raloxifene Evaluation study, a large prospective intervention trial in postmenopausal women with osteoporosis, offered the opportunity to compare vitamin D status and parathyroid function throughout many countries over the world. For this study, baseline data were available from 7564 postmenopausal women from 25 countries on 5 continents. All women had osteoporosis, i.e. bone mineral density (BMD) at femoral neck or lumbar spine was lower than t-score -2.5, or they had 2 vertebral fractures. Serum 25OHD was measured by RIA, and serum PTH was measured by immunoradiometric assay. BMD was measured by dual x-ray absorptiometry. The mean (+/-SD) serum 25OHD was 70.8 +/- 30.9 nmol/L. A low serum 25OHD (<25 nmol/L) was observed in 4.1% of all women in the Multiple Outcomes of Raloxifene Evaluation study, ranging from 0% in south east Asia (very few patients) to 8.3% in southern Europe. Serum 25OHD was between 25-50 nmol/L in 24.3% of the women. Serum 25OHD showed a significant seasonal relationship, with lower values in all regions in winter. Serum PTH correlated negatively with serum 25OHD (r = -0.25; P < 0.001). This significant negative correlation was observed in all regions. When serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, mean serum PTH levels were 4.8, 4.1, and 3.5 pmol/L, respectively (by ANOVA, P < 0.001). Similarly, mean alkaline phosphatase levels were 83.7, 79.1, and 75.7 U/L (P < 0.001), respectively, with increasing serum 25OHD. The effect of serum 25OHD on BMD was only significant for the BMD of the trochanter where a serum 25OHD level less than 25 nmol/L was associated with a 4% lower BMD. After 6 months of treatment with vitamin D(3) (400-600 IU/day) and calcium (500 mg/day), serum 25OHD increased from 70.8 +/- 29.8 to 92.3 +/- 28.6 nmol/L. Serum PTH decreased significantly after 6 months of treatment, and this decrease depended on baseline serum 25OHD. When baseline serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, serum PTH decreased by 0.8, 0.5, or 0.2 pmol/L, respectively (P < 0.001). In conclusion, serum 25OHD was less than 25 nmol/L in 4% of the women, and this was associated with a 30% higher serum PTH. In 24% of the women serum 25OHD was between 25-50 nmol/L, associated with a 15% higher level of serum PTH compared with women with a serum 25OHD greater than 50 nmol/L. A low serum 25OHD level was also associated with higher serum alkaline phosphatase and lower BMD of the trochanter. Treatment with vitamin D(3) and calcium increased serum 25OHD and decreased serum PTH significantly; the effect was greater for lower baseline serum 25OHD.


Do serum vitamin D levels correlate with Macular Edema or with Diabetic Retinopathy?
To compare serum vitamin D (25(OH)D) levels according to the presence of diabetic macular edema (DME) in Diabetes Mellitus (DM) patients with different retinopathy conditions. The files of all DM patients presenting for examination at the ophthalmology clinic between October 2018 and March 2020 were retrospectively examined. Data was collected from the files and included a comprehensive ophthalmological examination, laboratory results from fasting blood tests, and the internal medicine outpatient clinic examination. Patients were divided into two groups according to the presence of DME, they were divided into three groups in terms of retinopathy and DME, and in terms of retinopathy severity and presence of DME, they were divided into five groups. Ninety one (51.1%) of the age-sex matched participants were female and 87 (48.9%) were male. There was a statistically significant difference in vitamin D levels between the group with DME and the group without DME (p ≤ 0.001). In the comparison made according to the presence of retinopathy and DME; a significant difference was found between the DME group and the group with retinopathy but no DME (p ≤ 0.001). When the severity of retinopathy and the presence of DME were evaluated, a significant difference was found between the proliferative diabetic retinopathy (PDR) group with DME and the PDR group without DME in terms of vitamin D levels (p = 0.004). Our study shows that the presence of DME is associated with lower serum 25(OH)D levels.


National economic development and disparities in body mass index: a cross-sectional study of data from 38 countries.
Increases in body mass index (BMI) and the prevalence of overweight in low- and middle income countries (LMICs) are often ascribed to changes in global trade patterns or increases in national income. These changes are likely to affect populations within LMICs differently based on their place of residence or socioeconomic status (SES). Using nationally representative survey data from 38 countries and national economic indicators from the World Bank and other international organizations, we estimated ecological and multilevel models to assess the association between national levels of gross domestic product (GDP), foreign direct investment (FDI), and mean tariffs and BMI. We used linear regression to estimate the ecological association between average annual change in economic indicators and BMI, and multilevel linear or ordered multinomial models to estimate associations between national economic indicators and individual BMI or over- and underweight. We also included cross-level interaction terms to highlight differences in the association of BMI with national economic indicators by type of residence or socioeconomic status (SES). There was a positive but non-significant association of GDP and mean BMI. This positive association of GDP and BMI was greater among rural residents and the poor. There were no significant ecological associations between measures of trade openness and mean BMI, but FDI was positively associated with BMI among the poorest respondents and in rural areas and tariff levels were negatively associated with BMI among poor and rural respondents. Measures of national income and trade openness have different associations with the BMI across populations within developing countries. These divergent findings underscore the complexity of the effects of development on health and the importance of considering how the health effects of "globalizing" economic and cultural trends are modified by individual-level wealth and residence.


Plant interactions with multiple insect herbivores: from community to genes.
Every plant is a member of a complex insect community that consists of tens to hundreds of species that belong to different trophic levels. The dynamics of this community are critically influenced by the plant, which mediates interactions between community members that can occur on the plant simultaneously or at different times. Herbivory results in changes in the plant's morphological or chemical phenotype that affect interactions with subsequently arriving herbivores. Changes in the plant's phenotype are mediated by molecular processes such as phytohormonal signaling networks and transcriptomic rearrangements that are initiated by oral secretions of the herbivore. Processes at different levels of biological complexity occur at timescales ranging from minutes to years. In this review, we address plant-mediated interactions with multiple species of the associated insect community and their effects on community dynamics, and link these to the mechanistic effects that multiple attacks have on plant phenotypes.


Crack abuse during pregnancy: maternal, fetal and neonatal complication.
The aim of this study was to assess the effects of crack on pregnancy outcomes. We studied 88 crack user pregnant women in this study. These women were matched to a drug-free group (n = 90) chosen from the population of the same hospital. Maternal outcomes including preeclampsia, placenta abruption, gestational diabetes and preterm labor, and neonatal complication including low birth weight and low Apgar score in 5 min were compared in crack using and drug-free groups. Data were analyzed by SPSS software. Chi-square test and Student's t-test and Relative Risks (RRs) were used in this study. The results of our study showed that crack abuse during pregnancy was associated with higher rate of preeclampsia p = 0.003 (RR, 1.731; 95% CI, 1.777-2.545), placental abruption p = 0.001 (RR, 2.439; 95% CI, 1.369-4.343), preterm labor p < 0.000 (RR, 3.249; 95% CI, 2.053-5.141) and low birth weight p < 0.000 (RR, 2.179; 95% CI, 1.462-3.247). Crack abuse had significant influence on pregnancy outcomes. Crack appears to influence the prevalence of low birth weight, preterm labor, preeclampsia and placental abruption.


["Primary" reticulum cell sarcoma of the retina. II. Clinical diagnosis and course after radiotherapy (author's transl)].
A 59-year-old patient with "exudative chorioretinitis" progressed from confluent infiltration of the deep layers of the sensory retina, perivascularly and at the level of the pigmentepithelium to total infiltration of the vitreous. This occurred in spite of all the conventional antiinflammatory therapy. A clinical diagnosis of primary reticulum-cellsarcoma of the retina was made because diagnostic vitrectomy for cytologic study was refused. Radiotherapy with 4000 R by Betatron led to a rapid disappearance of the infiltration in the vitreous and retina and to diffuse subretinal scaring of the entire fundus (histologically confirmed). One year later the patient died in a psychiatrically disoriented state. It is thought that the course after radiotherapy and the histological findings support, although not definitely confirm, the clinical diagnosis. Clinical criteria may suffice for the diagnosis in desperate situations to initiate effective radiotherapy in these fatally ill patients.


A Review of Recent Evidence from Meal-Based Diet Interventions and Clinical Biomarkers for Improvement of Glucose Regulation.
In recent decades, the prevalence of diabetes has rapidly increased worldwide. Medical nutrition therapy has been identified as a major therapeutic support for diabetic patients, while preventive strategies in prediabetic or high-risk individuals have mainly focused on supplementation with bioactive compounds. Recently, meal-based interventions have been investigated as novel and safe long-term strategies for improving glucose regulation. However, evaluation of meal-based interventions is difficult since it requires analysis of sensitive markers. Biomarkers can also be used to identify individuals at risk for diabetes, which is important for disease prevention. In this review, we summarize current evidence from meal-based intervention studies conducted with the aim of improving glucose homeostasis in individuals at risk of diabetes using clinical biomarkers currently used to assess diabetic risk. Very low-calorie diets have significantly improved glucose regulation in obese adults and in adults with type 2 diabetes mellitus. In particular, changing the ratios of macronutrients through calorie restriction reduces fasting glucose level and hemoglobin A1c levels in patients with diabetes mellitus. However, this effect is limited in both obese and healthy adults. To date, multiple glucose-related markers have been identified as clinical biomarkers of diabetes. Additional clinical biomarkers include cholesterol levels, hematological markers, and inflammatory markers. Taken together, the evidence presented in this review may help for selection of clinical biomarkers for meal-based preventive approaches for non- or pre-diabetic individuals to prevent onset of diabetes.


Superhydrophobic Tipped Antimicrobial Photodynamic Therapy Device for the In Vivo Treatment of Periodontitis Using a Wistar Rat Model.
Limited options exist for treatment of periodontitis; scaling and root planing (SRP) are not sufficient to eradicate P. gingivalis and the resulting inflammatory disease. Chlorhexidine (CHX), used as an adjuvant to SRP, may reduce bacterial loads but leads to pain and staining, while evidence for its efficacy is lacking. Antibiotics are effective but can lead to drug-resistance. The rising concern of antibiotic resistance limits the future use of this treatment approach. This study evaluates the efficacy of a novel superhydrophobic (SH) antimicrobial photodynamic therapy (aPDT) device as an adjuvant to SRP for the treatment of periodontitis induced in a Wistar rat in vivo model relative to CHX. The SH-aPDT device comprises an SH silicone rubber strip coated with verteporfin photosensitizer (PS), sterilized, and secured onto a tapered plastic optical fiber tip connected to a red diode laser. The superhydrophobic polydimethylsiloxane (PDMS) strips were fabricated by using a novel soluble template method that creates a medical-grade elastomer with hierarchical surface roughness without the use of nanoparticles. Superhydrophobicity minimizes direct contact of the PS-coated surface with bacterial biofilms. Upon insertion of the device tip into the pocket and energizing the laser, the device generates singlet oxygen that effectively targets and eliminates bacteria within the periodontal pocket. SH-aPDT treatment using 125 J/cm2 of red light on three consecutive days reduced P. gingivalis significantly more than SRP-CHX controls (p < 0.05). Clinical parameters significantly improved (p < 0.05), and histology and stereometry results demonstrated SH-aPDT to be the most effective treatment for improving healing and reducing inflammation, with an increase in fibroblast cells and extracellular matrix and a reduction in vascularization, inflammatory cells, and COX-2 expression. The SH-aPDT approach resulted in complete disease clearance assessed 30 days after treatment initiation with significant reduction of the periodontal pocket and re-formation of the junctional epithelium at the enamel-cementum junction. PS isolation on a SH strip minimizes the potential for bacteria to develop resistance, where the treatment may be aided by the oxygen supply retained within the SH surface.


Wearable systems for health care applications.
Wearable systems can be broadly defined as mobile electronic devices that can be unobtrusively embedded in the user's outfit as part of the clothing or an accessory. In particular, unlike conventional mobile systems, they can be operational and accessed without or with very little hindrance to user activity. To this end they are able to model and recognize user activity, state, and the surrounding situation: a property, referred to as context sensitivity. Wearable systems range from micro sensors seamlessly integrated in textiles through consumer electronics embedded in fashionable clothes and computerized watches to belt worn PCs with a head mounted display. The wearable computing concept is part of a broader framework of ubiquitous computing that aims at invisibly enhancing our environment with smart electronic devices. The goal of the paper is to provide a broad overview of wearable technology and its implications for health related applications. We begin by summarizing the vision behind wearable computing. We then describe a framework for wearable computing architecture and the main technological aspects. Finally we show how specific properties of wearable systems can be used in different health related application domains. Wearable computing is an emerging concept building upon the success of today's mobile computing and communication devices. Due to rapid technological progress it is currently making a transition from a pure research stage to practical applications. Many of those applications are in health related domains, in particular, health monitoring, mobile treatment and nursing. Within the next couple of years wearable systems and more general ubiquitous computing will introduce profound changes and new application types to health related systems. In particular they will prove useful in improving the quality and reducing the cost of caring for the aging population.


Comparative effect of a 1 h session of electrical muscle stimulation and walking activity on energy expenditure and substrate oxidation in obese subjects.
It has previously been shown that low-frequency neuromuscular electrical stimulation (NMES) techniques can induce increases in energy expenditure similar to those associated with exercise. This study investigated the metabolic and cardiovascular effects of a 1 h session of lower limb NMES and compared cardiovascular response with that observed during walking in nine obese subjects (three males) (age = 43.8 ± 3.0 years; body mass index (BMI) = 41.5 ± 1.8 kg/m(2)). The NMES protocol consisted of delivering a complex pulse pattern to the thigh muscles for 1 h. The walking test consisted of five 4-min bouts starting at 2 km/h with 1 km/h increments up to 6 km/h. In both tests, an open-circuit gas analyser was used to assess O(2) consumption ([Formula: see text]O(2)), CO(2) production ([Formula: see text]CO(2)), respiratory exchange ratio (RER), and heart rate (HR). Rates of fat oxidation (RFO) and carbohydrate oxidation (CHO) were estimated by indirect calorimetry. One hour of NMES significantly increased [Formula: see text]O(2), HR, RER, and mean energy expenditure compared with resting values, reaching 8.7 ± 1.3 mL·min(-2)·kg(-1) (47% of [Formula: see text]O(2peak)), 114.8 ± 7.5 bpm, 0.95, and 318.5 ± 64.3 kcal/h, respectively. CHO, but not RFO, increased during 1 h of NMES. With NMES, CHO was greater and RFO was less than at all walking speeds except 6 km/h. Lactate also increased more with NMES, to 3.5 ± 0.7 mmol versus a maximum of 1.5 ± 0.3 mmol with the walking protocol. These results suggest that NMES can be used in an obese population to induce an effective cardiovascular exercise response. In fact, the observed increase in energy expenditure induced by 1 h of NMES is clinically important and comparable with that recommended in weight management programs.


A Finite Mixture Item Response Theory Model for Continuous Measurement Outcomes.
A mixture extension of Samejima's continuous response model for continuous measurement outcomes and its estimation through a heuristic approach based on limited-information factor analysis is introduced. Using an empirical data set, it is shown that two groups of respondents that differ both qualitatively and quantitatively in their response behavior can be revealed. In addition to the real data application, the effectiveness of the heuristic estimation approach under real data analytic conditions was examined through a Monte Carlo simulation study. The results showed that the heuristic estimation approach provided reliable parameter estimates and the model successfully converged above 80% when the sample size was 250 and above 90% when the sample size was 500 or 1,000 for most conditions.


Internalization of the TXA2 receptor alpha and beta isoforms. Role of the differentially spliced cooh terminus in agonist-promoted receptor internalization.
Thromboxane A2 (TXA2) potently stimulates platelet aggregation and smooth muscle constriction and is thought to play a role in myocardial infarction, atherosclerosis, and bronchial asthma. The TXA2 receptor (TXA2R) is a member of the G protein-coupled receptor family and is found as two alternatively spliced isoforms, alpha (343 residues) and beta (407 residues), which share the first 328 residues. In the present report, we demonstrate by enzyme-linked immunosorbent assay and immunofluorescence microscopy that the TXA2Rbeta, but not the TXA2Ralpha, undergoes agonist-induced internalization when expressed in HEK293 cells as well as several other cell types. Various dominant negative mutants were used to demonstrate that the internalization of the TXA2Rbeta is dynamin-, GRK-, and arrestin-dependent in HEK293 cells, suggesting the involvement of receptor phosphorylation and clathrin-coated pits in this process. Interestingly, the agonist-stimulated internalization of both the alpha and beta isoforms, but not of a mutant truncated after residue 328, can be promoted by overexpression of arrestin-3, identifying the C-tails of both receptors as necessary in arrestin-3 interaction. Simultaneous mutation of two dileucine motifs in the C-tail of TXA2Rbeta did not affect agonist-promoted internalization. Analysis of various C-tail deletion mutants revealed that a region between residues 355 and 366 of the TXA2Rbeta is essential for agonist-promoted internalization. These data demonstrate that alternative splicing of the TXA2R plays a critical role in regulating arrestin binding and subsequent receptor internalization.


Molecular Characterization of the Kamese Virus, an Unassigned Rhabdovirus, Isolated from Culex pruina in the Central African Republic.
Rhabdoviridae is one of the most diversified families of RNA viruses whose members infect a wide range of plants, animals, and arthropods. The members of this family are classified into 13 genera and >150 unassigned viruses. Here, we sequenced the complete genome of a rhabdovirus belonging to the Hart Park serogroup, the Kamese virus (KAMV), isolated in 1977 from Culex pruina in the Central African Republic. The genomic sequence showed an organization typical of rhabdoviruses with additional genes in the P-M and G-L intergenic regions, as already reported for the Hart Park serogroup. Our Kamese strain (ArB9074) had 98% and 78.8% nucleotide sequence similarity with the prototypes of the KAMV and Mossuril virus isolated in Uganda and Mozambique in two different Culex species, respectively. Moreover, the protein sequences had 98-100% amino acid similarity with the prototype of the KAMV, except for an additional gene (U3) that showed a divergence of 6%. These molecular data show that our strain of the KAMV is genetically close to the Culex annuliorus strain that was circulating in Uganda in 1967. However, this study suggests the need to improve our knowledge of the KAMV to better understand its behavior, its life cycle, and its potential reservoirs.


Academic stress and associated sociodemographic variables: A study of pre-university students in Karnataka, India.
Academic stress is a predominant phenomenon among grade 11 and 12 students. The performance in Grade 12 is important for entry to higher education programs in India. The purpose of the study was to assess the magnitude of the perceived academic stress and identify the main stressors and the sociodemographic variables associated with the perceived academic stress among adolescents enrolled in the science stream in coastal Karnataka. Upon Institutional Ethical Committee approval, a cross-sectional survey was carried out among pre-university students (science stream) of coastal Karnataka during February-April 2021. The study used Manipal Inventory of Academic Stress (MIAS) scale to collect data on perceived academic stress from 1859 students (response rate 68.3%). Stratified cluster sampling method was used to collect data from the study participants. IBM Statistical Package for the Social Sciences (SPSS) 26.0 was used to analyze the data. Descriptive statistics, unpaired t-test, one-way analysis of variance (ANOVA), and multiple linear regression analyses were used to study the association between academic stress and various demographic variables. The study revealed that 28% of the Grade 11 students and 26% of the Grade 12 students experienced high or extreme stress. The significant stressors were lack of time for revision, queries from neighbors or relatives, and parental expectations on academic performance. Gender, residence, and the medium of instruction until Grade 10 were associated with academic stress. Measures at the institutional and national levels are necessary to reduce the academic stress in higher secondary education. The integrated curriculum proposed in the National Educational Policy 2020 addresses a few stressors identified in this study.


The Ischemia and Reperfusion Injury Involves the Toll-Like Receptor-4 Participation Mainly in the Kidney Cortex.
The renal inflammatory response and kidney regeneration in ischemia-reperfusion injury (IRI) are associated with Toll-like receptor 4 (TLR4). Here we study the role of TLR4 during IRI in the renal cortex and medulla separately, using wild-type (TLR4-WT) and Knockout (TLR4-KO) TLR4 mice. We used 30 minutes of bilateral renal ischemia, followed by 48 hours of reperfusion in C57BL/6 mice. We measured the expression of elements associated with kidney injury, inflammation, macrophage polarization, mesenchymal transition, and proteostasis in the renal cortex and medulla by qRT-PCR and Western blot. In addition, we studied kidney morphology by H/E and PAS. Renal ischemia (30min) and reperfusion (48hrs) induced the mRNA and protein of TLR4 in the renal cortex. In addition, Serum Creatinine (SCr), blood urea nitrogen (BUN), Neutrophil gelatinase-associated lipocalin (NGAL), and acute tubular necrosis (ATN) were increased in TLR4-WT by IRI. Interestingly, the SCr and BUN had normal levels in TLR-KO during IRI. However, ATN and high levels of NGAL were present in the kidneys of TLR4-KO mice. The pro-inflammatory (IL-6 and TNF-α) and anti-inflammatory (Foxp3 and IL-10) markers increased by IRI only in the cortex of TLR4-WT but not in TLR4-KO mice. Furthermore, the M1 (CD38 and Frp2) and M2 (Arg-I, Erg-2, and c-Myc) macrophage markers increased by IRI only in the cortex of TLR4-WT. The TLR4-KO blunted the IRI-upregulation of M1 but not the M2 macrophage polarization. Vimentin increased in the renal cortex and medulla of TLR4-WT animals but not in the cortex of TLR4-KO mice. In addition, iNOS and clusterin were increased by IRI only in the cortex of TLR4-WT, and the absence of TLR4 inhibited only clusterin upregulation. Finally, Hsp27 and Hsp70 protein levels increased by IRI in the cortex and medulla of TLR4-WT and TRL4-KO lost the IRI-upregulation of Hsp70. In summary, TLR4 participates in renal ischemia and reperfusion through pro-inflammatory and anti-inflammatory responses inducing impaired kidney function (SCr and BUN). However, the IRI-upregulation of M2 macrophage markers (cortex), iNOS (cortex), IL-6 (medulla), vimentin (medulla), and Hsp27 (cortex and medulla) were independent of TLR4. The TLR4 inactivation during IRI prevented the loss of renal function due to the inactivation of inflammation response, avoiding M1 and preserving the M2 macrophage polarization in the renal cortex.


Identification of SRC as a potent drug target for asthma, using an integrative approach of protein interactome analysis and in silico drug discovery.
Network-biology inspired modeling of interactome data and computational chemistry have the potential to revolutionize drug discovery by complementing conventional methods. We consider asthma, a complex disease characterized by intricate molecular mechanisms, for our study. We aim to integrate prediction of potent drug targets using graph-theoretical methods and subsequent identification of small molecules capable of modulating activity of the best target. In this work, we construct the protein interactome underlying this disease: Asthma Protein Interactome (API). Using a strategy based on network analysis of the interactome, we identify a set of potential drug targets for asthma. Topologically and dynamically, v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC) emerges as the most central target in API. SRC is known to play an important role in promoting airway smooth muscle cell growth and facilitating migration in airway remodeling. From interactome analysis, and with the reported role in respiratory mechanisms, SRC emerges as a promising drug target for asthma. Further, we proceed to identify leads for SRC from a public database of small molecules. We predict two potential leads for SRC using ligand-based virtual screening methodology.


VASABI: Hierarchical User Profiles for Interactive Visual User Behaviour Analytics.
User behaviour analytics (UBA) systems offer sophisticated models that capture users' behaviour over time with an aim to identify fraudulent activities that do not match their profiles. Motivated by the challenges in the interpretation of UBA models, this paper presents a visual analytics approach to help analysts gain a comprehensive understanding of user behaviour at multiple levels, namely individual and group level. We take a user-centred approach to design a visual analytics framework supporting the analysis of collections of users and the numerous sessions of activities they conduct within digital applications. The framework is centred around the concept of hierarchical user profiles that are built based on features derived from sessions, as well as on user tasks extracted using a topic modelling approach to summarise and stratify user behaviour. We externalise a series of analysis goals and tasks, and evaluate our methods through use cases conducted with experts. We observe that with the aid of interactive visual hierarchical user profiles, analysts are able to conduct exploratory and investigative analysis effectively, and able to understand the characteristics of user behaviour to make informed decisions whilst evaluating suspicious users and activities.


Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer.
The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated. To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells. IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments. IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival. Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.